The largest-ever study of schizophrenia patients shows that the condition is driven by more than 100 genes – some that were expected, and some that require more research to explain.

The study, published online today in Nature, confirms that genes connected to regulating the brain chemical dopamine are involved in schizophrenia, as predicted. But so are genes involved in the immune system, and several associated with heavy smoking.

"Some are very familiar genes expressed in nerve cells, and some are results where you scratch your head and you know you have more work to do" to understand their role in schizophrenia, said Steven Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, which helped lead the study.

That doesn't mean that schizophrenia is caused by inflammation or cigarettes. Genes may play one role in the immune system and another in the brain, for instance, Hyman said.

The Stanley Center will be able to pursue more studies like this thanks to a donation of $650 million, scheduled to be announced early Tuesday. The money, from philanthropist Ted Stanley, will bring his total donations to the center up to approximately $825 million, Hyman said.

Stanley is the founder and chairman of MBI, a consumer products company that began by marketing a series of medals commemorating the 1969 moon landing.

Short-term, the donation — one of the largest ever to biomedical research — will be used to advance the genetic analysis of schizophrenia, bipolar disorder and related illnesses; and to study brain cells generated from patients' skin cells.

"Most importantly, the goal is not to end up with a list of genes, but with novel treatments," Hyman said via e-mail. To that end, he said, another member of the Stanley Institute, former Merck executive Ed Scolnick, has developed a program to discover new drugs through combining genetics, stem cell work and neurobiological data, Hyman said.

At this point, the identification of the 108 schizophrenia genes in the new study means much more to scientists than to patients. Patients will start to benefit, Hyman said, when scientists — and hopefully drug companies — use the genes to identify targets for drug treatments.

"In some sense, it's already giving us clues to the biology of this disease that ultimately will be exploitable to understand what is going wrong in the brain and most importantly for very much needed new treatments," Hyman said.

This isn't the first time that researchers have considered a link between the immune system and schizophrenia. Smaller genetic studies have hinted at a connection. People with schizophrenia often have signs of inflammation in their bloodstream, and relatives of those with autoimmune disorders have as much as 45% increased risk of developing schizophrenia, said Consuelo Walss Bass, an associate professor at the University of Texas Health Science Center in Houston.

The new study removes any doubt about the connection.

The genome-wide association study, or GWAS, looked for genes that were common across many of the 150,000 participants, nearly 37,000 of whom had the disease. The large number — and overrepresentation of those with schizophrenia — was crucial for scientists to see the contributions of multiple genes, each of which only contributes a little bit to schizophrenia.

About 1% of Americans have schizophrenia, a brain disorder that can lead to agitation, hearing voices and terrifying paranoia.

Studying so many patients requires the collaboration of many scientists and doctors, and is a "huge achievement," said Marcus Munafò, a professor of Biological Psychology at the University of Bristol in the United Kingdom, who wrote a commentary about the new study in Nature.

Most common diseases are the result of many genes interacting. GWAS studies help researchers identify genes that are important to a particular condition but may not be obvious in terms of function.

It's not clear yet why the genes associated with smoking are involved with schizophrenia, Munafò said, but knowing that they are could help researchers identify whether smoking actually increases risk, for instance, or whether there are lifestyle changes people could make to reduce their chances of getting schizophrenia, he said.

Because the study is so large, it's pretty certain that any gene that showed up in the study plays a significant role in schizophrenia, but not every gene important to the condition has been identified yet.

"Now we have 108 pieces, but maybe it's a 1,000-piece puzzle, so we have a long way to go," Hyman said.